The failure to treat metastatic
cancer with multidrug resistance is a major problem for successful
cancer therapy, and the molecular basis for the association of metastatic phenotype with resistance to
therapy is still unclear. In this study, we revealed that various metastatic
cancer cells showed consistently higher levels of antiapoptotic
proteins, including Bcl-2,
nuclear factor-kappaB, MDM2,
DNA-dependent protein kinase (
DNA-PK), and
epidermal growth factor receptor (EGFR), and lower levels of proapoptotic
proteins, including Bax and p53 than low metastatic parental cells. This was followed by chemo- and radioresistance in metastatic
cancer cells compared with their parental cells. EGFR and
DNA-PK activity, which are known to be associated with chemo- and radioresistance, were demonstrated to be mutually regulated by each other. Treatment with
PKI166, an EGFR inhibitor, suppressed
etoposide-induced activation of
DNA-PK in A375SM metastatic
melanoma cells. In addition,
PKI166 enhanced markedly the chemosensitivities of metastatic
cancer cell sublines to various anticancer drugs in comparison with those of low metastatic
cancer cells. These results suggest that the activities of
DNA-PK and EGFR, which is positively correlated with each other, may contribute to metastatic phenotype as well as
therapy resistance, and the EGFR inhibitor enhances the effect of anticancer drugs against
therapy-resistant metastatic
cancer cells via suppression of stress responses, including activation of
DNA-PK.